tailieunhanh - Báo cáo khoa học: Suppression of urokinase receptor expression by bikunin is associated with inhibition of upstream targets of extracellular signal-regulated kinase-dependent cascade

Our laboratory showed that bikunin, aKunitz-type protease inhibitor, suppresses 4b-phorbol 12-myristate 13-acetate (PMA)- or tumor necrosis factor-alpha (TNFa)-induced urokinase-type plasminogen activator (uPA) expression in different cell types. In addition to its effects on protease inhibition, bikunincouldbemodulatingother cellular events associated with the metastatic cascade. | Eur. J. Biochem. 269 3945-3957 2002 FEBS 2002 doi Suppression of urokinase receptor expression by bikunin is associated with inhibition of upstream targets of extracellular signal-regulated kinase-dependent cascade Hiroshi Kobayashi1 Mika Suzuki1 Naohiro Kanavama1. Takashi Nishida2 Masaharu Takiaawa2 and Toshihiko Terao1 1 Department of Obstetrics and Gynecology Hamamatsu University School of Medicine Hamamatsu Shizuoka Japan department of Biochemistry and Molecular Dentistry Okayama University Graduate School of Medicine and Dentistry Okayama Japan Our laboratory showed that bikunin a Kunitz-type protease inhibitor suppresses 4b-phorbol 12-myristate 13-acetate PMA - or tumor necrosis factor-alpha TNFa -induced urokinase-type plasminogen activator uPA expression in different cell types. In addition to its effects on protease inhibition bikunin could be modulating other cellular events associated with the metastatic cascade. To test this hypothesis we examined whether bikunin was able to suppress the expression of uPA rereptor uPAR mRNA and proiein in a human chondrosarcoma cell line HCS-2 8 and two human ovarian cancer cell lines HOC-I and HRA. The present study showed that a bikunin suppresses the expression of constitutive and PMA-induced uPAR mRNA and protein in a variety of cell types b an extracellular signal-regulated kinase ERK activation system is necessary for the PMA-induced increase in uPAR expression as PD098059 and U0126 which prevent the activation of MEK1 reduce the uPAR expression c bikunin markedly suppresses PMA-induced phosphorylation of ERK1 2 at the concentration that prevents uPAR expression but does not reduce total ERK1 2 antigen level d bikunin has no ability to inhibit overexpression of uPAR in cells treated with sodium vanadate and e we further studied the inhibition of uPAR expression by stable transfection of HRA cells with bikunin gene demonstrating that bikunin secretion is necessary for inhibition of

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